Project Summary/Abstract Bronchopulmonary dysplasia (BPD) affects 30% of the extremely premature infants and is associated with significantly increased morbidity and mortality in this vulnerable population. Its pathogenesis is incompletely understood. However, exposure of the premature lung to hyperoxia, inflammation, and ventilation is the principal underlying predisposing factor. And more importantly, there is no effective intervention to either prevent or treat BPD. Recent work from our laboratory has highlighted a key role for pulmonary alveolar interstitial fibroblast (AIF) in neonatal lung injury and repair in general and in the pathogenesis of BPD in particular. We have determined that transdifferentiation of AIF-to-myofibroblasts (MYF), as determined by the expression of the key nuclear transcription factor Peroxisome Proliferator-Activated Receptor (PPAR)g, is a key event in the pathobiology of BPD. Curcumin [1,7-bis (4'-hydroxy-3'-methoxyphenyl)-1,6-heptadiene-3,5-dione], a naturally occurring pigment derived from the Indian spice turmeric, has potent antioxidant and anti- inflammatory properties, which has also been shown to modulate PPARg signaling. However, its role in modulating PPARg signaling in the neonatal lung and in the prevention of BPD is not known. We hypothesize that curcumin, by up-regulating the homeostatic AIF PPARg signaling, will enhance neonatal lung maturation and will prevent hyperoxia-induced neonatal lung injury, and therefore prevent BPD. In a rat model, our preliminary data clearly suggest that curcumin accelerates neonatal lung maturation and abrogates hyperoxia- induced neonatal lung injury. Using state-of-the-art methods, we will determine if and how 1) curcumin enhances neonatal lung maturation and 2) protects against hyperoxia-induced neonatal lung injury. In particular, we will determine if the protection is mediated by blocking hyperoxia-induced activation of TGF-2 signaling and lung cellular apoptosis. The proposed studies are likely to establish the effectiveness of a naturally occurring antioxidant and anti-inflammatory agent to block hyperoxia-induced lung damage, which can help decrease the prevalence and severity of BPD and improve lung function and quality of life in this vulnerable population. These preclinical studies will facilitate future translation of curcumin therapy to prevent BPD. PUBLIC HEALTH RELEVANCE: Project Narrative Up to 30% of the extremely premature infants have chronic lung disease of prematurity, called Bronchopulmonary Dysplasia. There infants are unable to oxygenate their blood adequately, which leads to significantly increased life-long morbidity and mortality in this vulnerable population. Though, at present, there is no effective preventive or therapeutic intervention, the proposed studies are likely to establish the effectiveness of curcumin, the active ingredient of the Indian spice turmeric, in effectively preventing bronchopulmonary dysplasia.\